Historical Background
Influenza is an acute infectious respiratory disease of man, commonly encountered in epidemic form, caused by an influenza virus. What is now called influenza or "flu" is readily recognized in dramatic descriptions covering many centuries of epidemics arising explosively in a population and spreading rapidly and widely over large areas.
There have been various pandemics or world visitations of influenza. For example, between 1800 or 1875, 1889-92 and in 1918-19, there occurred serious pandemics or influenza. Influenza pandemics take place in waves, starting in certain parts of the world, then spreading to others. One of the most peculiar and intriguing features of the epidemiology of influenza is its periodicity. In North America and Europe, for example, outbreaks of influenza occur every two or three years, usually between December and February. Three distinct immunologic types of influenza virus A, B and C have been classified. The severe outbreaks are practically always caused by influenza virus A. The seriousness of influenza pandemics by influenza virus A. The seriousness of influenza pandemics has been the reason for the establishment of the World Influenza Center in London, England and the Strain Study Center for the Americas, Brooklyn, N.Y., which monitor, carry out research and classify viruses, In 1933, the influenza virus was isolated and was designated as the original or classic A.sub.o strain (WS) or PR8 strain. In 1946-47, a new mutant or antigenic variant became prominent and received the name of A prime. The first recognized A prime outbreak was in Japan and Korea in late 1946. These A prime strains have, with perhaps some exceptions, displaced the original strains as the cause of epidemic influenza in various parts of the world. From 1946-47 to 1957, various different strains of A prime of influenza virus appeared in various parts of the world and disease broke out, progressing from one part to the other. In 1957-1958, a new variant of type A, A.sub.2, caused widespread infection in Asia and soon was introduced in Europe; the term Asiatic influenza was applied to this epidemic. Each one of these mutants lasted about 10-14 years. In 1968, there appeared yet another type of influenza virus, the Hong Kong type, A.sub.HK, which reached Europe in 1969 after having spread through the United States, where it was reported more than 40,000,000 persons were afflicted to various degrees of seriousness, over 35,000 fatally. Influenza represents one of the most serious causes of very significant economic loss as patients remain away from their normal productive work.
The Hong Kong virus is the prevailing subtype influenza virus prevailing now in the world, and it is expected to remain the infectious active type at least until approximately 1978-1980. The invention provides, as one its important but not sole contribution, a remedy against this type of flu.
Throughout this patent, the nomenclature generally used for the various viruses is that adopted by the Virus Subcommittee of the International Nomenclature Committee. In Table I below, Influenza Viruses, there is presented a partial listing of the various types of subtypes of viruses with an accompanying designation, to which reference is made from time to time in the description of this invention.
TABLE I ______________________________________ INFLUENZA VIRUSES ______________________________________ A/Hong Kong/1/68 (H.sub.3 N.sub.2) A/Hong Kong 107/71 (H.sub.3 N.sub.2) A/NT/60/1968 (H.sub.3 N.sub.2) A/England/42/72 (H.sub.3 N.sub.2) A/England/878/69 (H.sub.3 N.sub.2) A/Finland/2/72 (H.sub.3 N.sub.2) ______________________________________
The H.sub.3 designates the hemagglutinin which is one of the surface antigens of the virus. A description of the characteristics of the hemagglutinin is found in Hoyle, referred to below, at pages 81 to 89.
The N.sub.2 designates the neuraminidase which is an enzyme antigen of the virus. A description of the nature of the neuraminidase and other characteristics of this antigen of the virus strains is found in Hoyle, referred to below, at pages 91 to 95, which is incorporated herein by reference.
One of the most puzzling and frustrating features of influenza virus is its continuous evolution or what has been called its "plasticity". From year to year, the existing virus strain "drifts"; it gradually evolves so that the chemical defenders or antibodies generated in the body by the introduction of the antigers by way of the disease or by vaccination from the original strain become less and less effective. Vaccine producers are engaged in a continuous race to keep up with this virus drift, collecting new strains as they appear in various parts of the world and preparing vaccines therefrom. The protection afforded by natural immunity or by vaccination is constantly overtaken by another viral variant. Indeed, the influenza virus appears from year to year as a slightly variant structure so that the patient who has been inoculated or who has had the virus the prior year finds himself defenseless, or rather with outmoded defenses to the new variant. This explains why a person who has had the flu can have it repeatedly upon the occurrence of different substrains through inoculated. This also now explains the fact, puzzling until now, why a vaccine which may have been thought to be effective when it was manufactured in response to a particular substrain, is in fact not as effective any longer to give the desired immunity when injected into a patient since that patient can already be inflicted with a substrain which is one step ahead of the vaccine which has been given.
The versatility of the influenza strains is apparent from the fact that the world has known since 1933 mutants A.sub.O, A.sub.1, A.sub.2, and A.sub.HK and for each type a series of variants, or subtypes, differing enough from the initial strain to defy the natural defense or immunization of the patients. A single subtype or variant is established at any given time in the world, presently, as explained above, the Hong Kong sub-type. Serological studies of populations have established that infection by a new variant immunizes effectively against the preceding variants of the same sub-type, however, the latter preceding variants do not confer efficient immunity against strains that are prevailing at that time, nor those which follow. That strain is already one step ahead of the vaccine. In effect, it appears that immunity is playing a role of a selection agent favoring the survival of new subtype mutants, which then can escape and spread to epidemic proportions. These mutants are more resistant to the vaccine used at that time, a property which the precursors did not possess. In effect, then, each new generation of substrains replaces its previous generation and is at least partially unaffected by the vaccine until it, in turn, is replaced by a new generation of substrains.
The gradual and continuous evolution, which is most frustrating, of a strain up to a certain stage has been suggested to be due to the evolution of the structure responsible for antigen determining factors specific of the haemagglutinine of the virus, which is responsible of the ability of the virus to agglutinate red blood cells, which is a characteristic feature of an influenza virus, and of the Hong Kong type which is of special concern here. The vaccine to provide the desired immunity has eluded researchers until now.
An explanation which has been suggested of the above gradual and continuous evolution rests on the theory that the influenza virus may be considered as having an antigenic area on a viral coat protein which may be thought of as a small number of amino acid side chains jutting out of the surface. As the virus strain drifts from year to year, the amino acid arrangement is thought to vary up to a structure which affords no further possibility for drifting, next change then consisting in a fundamental mutation yielding a totally different sub-type of strains.
Within a same sub-type however it has been found that the antibodies which are elicited by the antigenic fraction of an original strain of the Hong Kong subtype in 1968, are less able to combine or conform with the variant which succeeded to it in view of the change in the amino acids of the antigen, if the above explanation is adhered. The greater the changes in the amino acid structure, the lesser the ability of the antibodies which were active against the antigenic fraction of the original strain to combine or conform with the corresponding variants, and therefore the greater their ineffectiveness against the subsequent variants, that is, in the example under consideration, influenza viruses which established or occurred throughout the world in 1970, 1972, and which are expected to occur in 1974 and so on to 1980.
It has however been found that, conversely, antibodies developed in the body of a living being, as a result of exposure to more recent strains happen to be effective against past strains belonging to the same sub-type.
For the sake of classification the strains and variants of a same sub-type are distinguished from one another by varying degrees of "seniority", the strains which appeared most recently being "senior" with respect to the preceding ones of the sub-type concerned. Conversely a given strain which preceded more recent ones in the sub-type development is "junior" with respect to the latter. The antibodies induced by a given strain are not only effective against that strain itself, but against all strains which are "junior" with respect to that given strain. For instance a Hong Kong strain recently isolated, namely variant A.sub.HK England 42/72 causes in man the formation of antibodies which are not effective not only against the strain, but against all other strains of the primitive Hong Kong sub-type which preceded it, or junior thereto. However, the antibodies elicited by strain A.sub.HK England 42/72 are expected to be of limited effectiveness or even to be ineffective against strains of the Hong Kong sub-type which shall be forthcoming in nature and which, accordingly, will be "senior" with respect to A.sub.HK England 42/72.